6a2p: Difference between revisions

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-'''Unreleased structure'''
-The entry 6a2p is ON HOLD  until Paper Publication
+==Crystal structure of quadruple mutant (N51I+C59R+S108N+I164L) Plasmodium falciparum DHFR-TS complexed with BT3, NADPH, and dUMP==
+<StructureSection load='6a2p' size='340' side='right'caption='[[6a2p]], [[Resolution|resolution]] 2.60&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[6a2p]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Plasmodium_falciparum Plasmodium falciparum]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6A2P OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6A2P FirstGlance]. <br>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.6&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=9RR:5,5-[propane-1,3-diylbis(oxy-4,1-phenylene)]bis(6-ethylpyrimidine-2,4-diamine)'>9RR</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene>, <scene name='pdbligand=UMP:2-DEOXYURIDINE+5-MONOPHOSPHATE'>UMP</scene></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6a2p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6a2p OCA], [https://pdbe.org/6a2p PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6a2p RCSB], [https://www.ebi.ac.uk/pdbsum/6a2p PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6a2p ProSAT]</span></td></tr>
+</table>
+== Function ==
+[https://www.uniprot.org/uniprot/D9N170_PLAFA D9N170_PLAFA] Bifunctional enzyme. Involved in de novo dTMP biosynthesis. Key enzyme in folate metabolism (By similarity).[PIRNR:PIRNR000389]
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+The S108N mutation of dihydrofolate reductase (DHFR) renders Plasmodium falciparum malaria parasites resistant to pyrimethamine through steric clash with the rigid side chain of the inhibitor. Inhibitors with flexible side chains can avoid this clash and retain effectiveness against the mutant. However, other mutations such as N108S reversion confer resistance to flexible inhibitors. We designed and synthesized hybrid inhibitors with two structural types in a single molecule, which are effective against both wild-type and multiple mutants of P. falciparum through their selective target binding, as demonstrated by X-ray crystallography. Furthermore, the hybrid inhibitors can forestall the emergence of new resistant mutants, as shown by selection of mutants resistant to hybrid compound BT1 from a diverse PfDHFR random mutant library expressed in a surrogate bacterial system. These results show that it is possible to develop effective antifolate antimalarials to which the range of parasite resistance mutations is greatly reduced.
-Authors: Chitnumsub, P., Jaruwat, A., Tarnchampoo, B., Yuthavong, Y.
+Hybrid Inhibitors of Malarial Dihydrofolate Reductase with Dual Binding Modes That Can Forestall Resistance.,Tarnchompoo B, Chitnumsub P, Jaruwat A, Shaw PJ, Vanichtanankul J, Poen S, Rattanajak R, Wongsombat C, Tonsomboon A, Decharuangsilp S, Anukunwithaya T, Arwon U, Kamchonwongpaisan S, Yuthavong Y ACS Med Chem Lett. 2018 Nov 7;9(12):1235-1240. doi:, 10.1021/acsmedchemlett.8b00389. eCollection 2018 Dec 13. PMID:30613332<ref>PMID:30613332</ref>
-Description: Crystal structure of quadruple mutant (N51I+C59R+S108N+I164L) Plasmodium falciparum DHFR-TS complexed with BT3, NADPH, and dUMP
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Yuthavong, Y]]
+<div class="pdbe-citations 6a2p" style="background-color:#fffaf0;"></div>
-[[Category: Jaruwat, A]]
-[[Category: Chitnumsub, P]]
+==See Also==
-[[Category: Tarnchampoo, B]]
+*[[Dihydrofolate reductase 3D structures|Dihydrofolate reductase 3D structures]]
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Large Structures]]
+[[Category: Plasmodium falciparum]]
+[[Category: Chitnumsub P]]
+[[Category: Jaruwat A]]
+[[Category: Tarnchampoo B]]
+[[Category: Yuthavong Y]]